Non–Cell-Autonomous Mechanisms and Systemic Interactions in Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder caused by a deficiency of the survival motor neuron (SMN) protein. Traditionally, it has been classified as a motor neuron disease. Over the past decade, however, numerous non-motor neuronal and non-neural pathologies reported in both SMA patients and mouse models have led to its redefinition as a systemic disorder. Although SMN protein expression outside the central nervous system (CNS) is well-established, it remains controversial whether its functional loss in non-neuronal cells/tissues merely represents a comorbidity or actively contributes to driving motor neuron degeneration. This review summarizes key evidence supporting the non-cell-autonomous death of motor neurons in SMA. Based on these lines of evidence, we propose three potential pathways for pathological transmission: (1) neuroinflammatory and neurotoxicity signaling mediated by glial cells, (2) aberrant retrograde signaling from the neuromuscular junction, and (3) modulation of the CNS by peripheral factors via the circulatory system. Future studies should focus on identifying critical peripheral tissues involved in SMA pathogenesis, elucidating the molecular mechanisms by which SMN deficiency leads to dysfunction in these tissues, and characterizing key mediators that influence motor neuron survival. In the current era where SMN-enhancing therapies have significantly improved patient survival, a deeper understanding of non-cell-autonomous mechanisms, and targeting them, represents a crucial step toward achieving curative strategies for SMA.